Physicochemically and Pharmacokinetically Stable Nonapeptide KISS1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity

• Published in: Journal of medicinal chemistry 2014-07, Vol.57 (14), p.6105-6115
• Main Authors: Asami, Taiji, Nishizawa, Naoki, Matsui, Hisanori, Takatsu, Yoshihiro, Suzuki, Atsuko, Kiba, Atsushi, Terada, Michiko, Nishibori, Kimiko, Nakayama, Masaharu, Ban, Junko, Matsumoto, Shin-ichi, Tarui, Naoki, Ikeda, Yukihiro, Yamaguchi, Masashi, Kusaka, Masami, Ohtaki, Tetsuya, Kitada, Chieko
• Format: Article
• Language: English
• Subjects: Animals; Chemistry, Physical; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Humans; Kisspeptins - administration & dosage; Kisspeptins - chemistry; Kisspeptins - pharmacology; Male; Molecular Conformation; Oligopeptides - administration & dosage; Oligopeptides - chemistry; Oligopeptides - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - agonists; Receptors, Kisspeptin-1; Structure-Activity Relationship; Testosterone - antagonists & inhibitors; Testosterone - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5005489

Modifications of metastin(45–54) produced peptide analogues with higher metabolic stability than metastin(45–54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45–54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic–pituitary–gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases.